In collaboration with J. Schneekloth (NCI) we have subjected a number of riboswitches to high-throughput screening employing a library of immobilized compounds. This methodology has revealed several lead compounds that bind specifically to particular bacterial riboswitches. We determined co-crystal structures of these leads bound to the RNAs, and using the structures, designed second-generation compounds. Functional and structural analyses of these compounds in turn demonstrated how small perturbations in the structures of ligands can affect their mode of interaction with regulatory RNAs. Publications describing this work are in preparation.